The invention relates to a method for sterilization of a polymerizable monomer, in particular to sterilization of a monomer for radical polymerization. The invention also relates to mixtures containing a polymerizable monomer, in particular a monomer for radical polymerization, a kit for producing bone cement containing one of these mixtures, and a bone cement paste containing one of these mixtures.
Conventional poly(methylmethacrylate) bone cements (PMMA bone cements) have been known for decades and are based on the ground-breaking work of Sir Charnley (Charnley, J.: “Anchorage of the Femoral Head Prosthesis of the Shaft of the Femur.” J. Bone Joint Surg. 42: 28-30 (1960)).
The basic structure of PMMA bone cements has remained the same ever since. PMMA bone cements consist of a liquid monomer component and a powder component. The monomer component generally contains (i) the monomer, methylmethacrylate, and (ii) an activator (e.g. N,N-dimethyl-p-toluidine) dissolved therein. The powder component comprises (i) one or more polymers that are made by polymerization, preferably suspension polymerization, based on methylmethacrylate and co-monomers, such as styrene, methylacrylate or similar monomers, (ii) a radio-opaquer, and (iii) an initiator, (e.g. dibenzoylperoxide). Mixing the powder component and the monomer component, the polymers of the powder component in the methylmethacrylate swell which generates a dough that can be shaped plastically. Simultaneously, the activator, N,N-dimethyl-p-toluidine, reacts with dibenzoylperoxide which disintegrates and forms radicals in the process. The radicals formed trigger the radical polymerization of the methylmethacrylate. Upon advancing polymerization of the methylmethacrylate, the viscosity of the cement dough increases until the cement dough solidifies and thus is cured.
German Patent DE 10 2007 050 762 B3 proposes a kit for producing bone cement comprising two pastes as an alternative to the conventional powder-liquid polymethylmethacrylate bone cements. These pastes each contain a polymerizable monomer, such as, for example, a methacrylate monomer for radical polymerization, a polymer soluble in the methacrylate monomer, and a particulate polymer insoluble in the methacrylate monomer. In addition, one of these pastes contains a radical polymerization initiator, whereas the other paste comprises a polymerization activator. As a result of the selected composition, the bone cement produced from these pastes possesses sufficiently high viscosity and cohesion in order to withstand the pressure from bleeding until it is fully cured. When the two pastes are mixed, the polymerization initiator reacts with the accelerator to form radicals that initiate the radical polymerization of the methacrylate monomers. Owing to the advancing polymerization, the paste is cured while the methacrylate monomers are consumed. The pastes contained in the kit for producing bone cement are non-aqueous systems. Accordingly, the pastes contain at most only traces of water.
PMMA bone cements are medical products of class IIb, or medical products of class III if antibiotics are added. In order to ensure the safety of the patients, the PMMA bone cements may be marketed in sterile condition in a doubly-sterile package only. In conventional PMMA bone cements consisting of a liquid monomer component and a powder component, the powder component is sterilized by subjecting it to ethylene oxide. Sterilization of the powder component by gamma irradiation is customary as well.
Often used for producing the monomer component, the polymerizable monomer, methylmethacrylate, is biocidal for most vegetative microbial life forms due to its lipophilic and thus denaturing properties. Therefore, these micro-organisms cannot exist in anhydrous methylmethacrylate. However, aside from the vegetative forms, micro-organisms also have generative forms, such as endospores. These generative survival forms of micro-organisms are formed by gram-positive bacteria, in particular of the Bacillus and Clostridium genus, as a means of persisting during unfavorable living conditions. In their resting state, endospores have no active metabolism and possess a multi-layered spore capsule that largely protects the core of the spore from the action of chemicals and other environmental effects. This renders spores extremely resistant to the action of heat and chemicals (Borick, P. M.: “Chemical Sterilizers,” Adv. Appl. Microbiol. 10: 291-312 (1968); Gould, G. W.: “Recent Advances in the Understanding of Resistance and Dormancy in Bacterial Spores,” J. Appl. Bacteriol. 42: 297-309 (1977); Gould, G. W.: “Mechanisms of Resistance and Dormancy,” in Hurst, A. and Gould, G. W. (ed.), The Bacterial Spore, Academic Press, Inc. New York, 2:173-209 (1983)). Due to their high resistance, endospores are used as bio-indicators for validation and control of the efficacy of sterilization processes. This is based on the assumption that the inactivation of endospores is indicative of all vegetative microbial forms of life being killed. Endospores of gram-positive bacteria are classified in international resistance class III. Resistance class I includes non-spore-forming bacteria and vegetative forms of spore-forming bacteria and resistance class II includes spores that are killed within a few minutes in a flow of steam at 105° C. In accordance with DAB 2008 (Deutsches Arzneimittelbuch—German Medicine Book), all micro-organisms of resistance classes I-III must be killed or inactivated irreversibly.
Accordingly, there is a fundamental need to have methods for efficient sterilization of polymerizable monomers, in particular of monomers for radical polymerization.
Methods for sterilization of polymerizable monomers are known in the field of medical products. It is common to use physical sterilization methods for sterilization of medical products. In particular gamma irradiation, electron bombardment, UV irradiation, heat sterilization, and autoclaving with pressurized steam need to be mentioned in this context. However, these sterilization methods are inherently disadvantageous due to the extensive use of equipment and process resources required by them. Sterilization of polymerizable monomers by means of these physical sterilization methods is inapplicable for other reasons as well though. For example, subjecting the materials to heat, gamma irradiation or X-ray irradiation would initiate radical polymerization of the polymerizable monomers which would result in inadvertent premature curing of the bone cement. Steam sterilization, in contrast, would result in hydrolysis of the polymerizable monomers which would prevent polymerization of the polymerizable monomers.
Sterilization of polymerizable monomers is often attained through sterile filtration and subsequent aseptic packing. However, the aseptic production of polymerizable monomers is very expensive. Another associated problem is that viruses cannot be removed through sterile filtration. Moreover, sterilization of pastes for producing bone cement by means of sterile filtration is not feasible due to the high viscosity of the pastes and the radio-opaquers and filling agents contained in the pastes.
Aside from these physical methods, it is customary to use chemical compounds for sterilization of medical products. These include, for example, ethylene oxide, formaldehyde, glutardialdehyde, o-phthaldialdehyde, hypochlorite, chlorine dioxide, peracetic acid, and hydrogen peroxide. However, the use of these compounds is associated with significant disadvantages. For example ethylene oxide is sporocidal only in the presence of moisture such that its use in the absence of water does not result in the desired sterilization effect. Moreover, pastes for producing bone cement are usually available in closed diffusion-tight film pouches or closed plastic cartridges. Ethylene oxide is incapable of penetrating into these containers, however the packaged pastes cannot be sterilized by this method. In contrast, aldehydes are usually applied as aqueous solutions or in the gaseous state in the case of formaldehyde due to their mechanism of action. Peracetic acid and hydrogen peroxide are strong oxidizing agents which are also used in the form of aqueous solutions. However, for this reason, these compounds are not suitable for sterilization of mixtures that must contain only small amounts of water, if any. Chlorine-based compounds are usually very effective sterilization agents. They are disadvantageous though in that chlorine-containing secondary products remain in the medical product after sterilization.
It is known from pharmaceutical industry that aqueous protein solutions, such as, e.g., vaccines, are very sensitive to the effects of oxidizing sterilization agents and various physical sterilization methods, for example sterilization with gamma radiation. For this reason, aqueous protein solutions often have small amounts of the acylating agent, β-propiolactone, added to them for the purpose of sterilization. β-propiolactone can be used inactivate both viruses and spores, in particular endospores. These effects are likely to occur due to acylation of the amino groups of DNA/RNA or proteins. The water present as solvent is capable of slowly decomposing zβ-propiolactone such that no active β-propiolactone is present any longer in aqueous protein solutions after just a short period of time. The principle of sterilization of aqueous protein solutions by means of acylating agents, such as β-propiolactone, is based on the fact that spores can swell in small amounts of aqueous media. This swelling renders the double walls of spores permeable to acylating agents, such that the acylating agents can penetrate into the spores and be effective therein.
However, swelling of the spores is not feasible in mixtures containing a polymerizable monomer and only small quantities of water, if any. Therefore, swelling cannot be used in preparation of the penetration of the acylating agent into spores. Accordingly, sterilization of these mixtures by means of acylating agents, such as β-propiolactone, appears not to be feasible.